Epidermal Growth Factor Receptor pathway substrate No. 8 (EPS8) is phosphorylation substrate of multiple receptor and non-receptor tyrosine kinases, first discovered by Fazioli et al. in Epidermal Growth Factor Receptor (EGFR), signaling pathways of mice fibroblast NIH3T3. Recent studies showed that EPS8 is unusually overexpressed in tissues and cells of various solid tumors (e.g. cervical cancer; colorectal cancer, pituitary tumor, oral squamous cell carcinoma, pancreatic ductal cancer, breast cancer, thyroid cancer, esophageal cancer and glioblastoma, etc.) and hematological malignancies (e.g. multiple myeloma, lymphoma, acute myeloid leukemia, mixed lineage leukemia or acute lymphoid leukemia), whereas lower or not expressed in normal tissues and cells. Further studies showed that EPS8 promotes tumor cell proliferation by regulating cell cycle, facilitates tumor cell metastasis by participating in cell pseudopodia formation and interacting with actin, and correlates with patient prognosis by influencing tumor cell resistance against chemotherapeutic drug (Li Y*, Xue T He Y, Du J. Novel oncoprotein EPS8: a new target for anticancer therapy [J] Future Oncology, 2013 October; 9 (10): 1587-94.). Therefore, EPS8 has become a new target in monitoring and treatment of the tumor, and provides a brand new road for tumor targeting therapy.
Among the inhibitors targeting different structural domains of EGFR, such as Herceptin (Herceptin, trastuzumab) targeting extracellular domain and Gefitinib (Iressa, gefitinib) targeting at kinase domain, most of them possess shortcomings in poor specificity, drug resistance, and severe side-effects, albeit their clinical application has achieved encouraging efficacy. Therefore, it is imperative that much safer, more effective, and more specific anti-cancer drugs are developed to meet the urgent needs in clinical practice. However, unlike the other growth factor receptors, the juxtamembrane domain of EGFR plays an “activating” rather than “self-restricting” role towards kinase domain (Jura N et al. Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment [J] Cell, 2009, 137 (7):1293-1307). Novel inhibitors targeting juxtamembrane domain possess better specificity and selectivity, which provide a novel target for malignant tumor diseases. Compared with above small molecular inhibitors, peptide inhibitors own a variety of merits, such as higher activity, lower dose, less toxicity, and amino acids as end-product of drug metabolism, which have already become a hot topic in therapy targeting tumors.